Spatiotemporal regulation of Ras activity provides directional sensing.
Cells' ability to detect and orient themselves in chemoattractant gradients has been the subject of numerous studies, but the underlying molecular mechanisms remain largely unknown [1]. Ras activation is the earliest polarized response to chemoattractant gradients downstream from heterotrimeric G proteins in Dictyostelium, and inhibition of Ras signaling results in directional migration defects [2]. Activated Ras is enriched at the leading edge, promoting the localized activation of key chemotactic effectors, such as PI3K and TORC2 [2-5]. To investigate the role of Ras in directional sensing, we studied the effect of its misregulation by using cells with disrupted RasGAP activity. We identified an ortholog of mammalian NF1, DdNF1, as a major regulator of Ras activity in Dictyostelium. We show that disruption of nfaA leads to spatially and temporally unregulated Ras activity, causing cytokinesis and chemotaxis defects. By using unpolarized, latrunculin-treated cells, we show that tight regulation of Ras is important for gradient sensing. Together, our findings suggest that Ras is part of the cell's compass and that the RasGAP-mediated regulation of Ras activity affects directional sensing.
Zhang
Sheng
S
Section of Cell and Developmental Biology Division of Biological Sciences Center for Molecular Genetics University of California, San Diego 9500 Gilman Drive La Jolla, CA 92093-0380 USA.
Charest
Pascale G
PG
Section of Cell and Developmental Biology Division of Biological Sciences Center for Molecular Genetics University of California, San Diego 9500 Gilman Drive La Jolla, CA 92093-0380 USA.
Firtel
Richard A
RA
Section of Cell and Developmental Biology Division of Biological Sciences Center for Molecular Genetics University of California, San Diego 9500 Gilman Drive La Jolla, CA 92093-0380 USA.
D000818:Animals; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D004023:Dictyostelium / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D017125:Genes, Protozoan; D011905:Genes, ras; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D002630:Chemotactic Factors; D025542:Neurofibromin 1; D015800:Protozoan Proteins; C424065:rasG protein, Dictyostelium; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins